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Stimuli associated with high reward modulate perception and such value-driven effects have been shown to originate from the modulation of the earliest stages of sensory processing in the brain. In natural environments objects comprise multiple features (imagine a rolling soccer ball, with its black and white patches and the swishing sound made during its motion), where each feature may signal different associations with previously encountered rewards. How perception of such an object is affected by the value associations of its constituent parts is unknown. The present study compares intra- and cross-modal value-driven effects on behavioral and electrophysiological correlates of visual perception. Human participants first learned the reward associations of visual and auditory cues. Subsequently, they performed a visual orientation discrimination task in the presence of previously rewarded visual or auditory cues (intra- and cross-modal cues, respectively) that were concurrently presented with the target stimulus. During the conditioning phase, when reward associations were learned and reward cues were the target of the task, reward value of both modalities enhanced the electrophysiological correlates of sensory processing in visual cortex. During the post-conditioning phase, when reward delivery was halted and previously rewarded stimuli were task-irrelevant, cross-modal value-enhanced behavioral measures of visual sensitivity whereas intra-modal value led to a trend for suppression. A similar pattern of modulations was found in the simultaneously recorded event-related potentials (ERPs) of posterior electrodes. We found an early (90-120 ms) suppression of ERPs evoked by high-value, intra-modal stimuli. Cross-modal cues led to a later value-driven modulation, with an enhancement of response positivity for high-compared to low-value stimuli starting at the N1 window (180-250 ms) and extending to the P3 (300-600 ms) responses of the posterior electrodes. These results indicate that visual cortex is modulated by the reward value of visual as well as auditory cues. Previously rewarded, task-irrelevant cues from the same or different sensory modality have a different effect on visual perception, as intra-modal high-value cues may interfere with the target processing, whereas cross-modal high-value cues boost the perception of the target.

Summary The p53 tumor suppressor pathway is frequently inactivated in human cancers. However, there are some cancer types without commonly recognized alterations in p53 signaling. Here we report that histone demethylase KDM5A is involved in the regulation of p53 activity. KDM5A is significantly amplified in multiple types of cancers, an event that tends to be mutually exclusive to p53 mutation. We show that KDM5A acts as a negative regulator of p53 signaling through inhibition of p53 translation via suppression of a subgroup of eukaryotic translation initiation genes. Genetic deletion of KDM5A results in upregulation of p53 in multiple lineages of cancer cells and inhibits tumor growth in a p53-dependent manner. In addition, we have identified a regulatory loop between p53, miR-34, and KDM5A, whereby the induction of miR-34 leads to suppression of KDM5A. Thus, our findings reveal a mechanism by which KDM5A inhibits p53 translation to modulate cancer progression., Graphical Abstract, Highlights • Genetic amplification of KDM5A tends to be negatively correlated with TP53 alterations • KDM5A inhibits p53 protein translation by suppressing a subset of translation genes • KDM5A regulates tumor growth in a p53-dependent manner • miR-34 targets KDM5A expression, Molecular Mechanism of Gene Regulation; Cancer

This study carried out leucaena torrefaction by using microwave heating to investigate the fuel properties of biochar and the energy efficiency of the technique. Both maximum temperature and heating rate increased with increasing microwave power level. Processing time was also an important operational parameter, but its effect was weaker than that of microwave power. The heating value of torrefied product was higher at higher power level and longer processing time, but the mass and energy yields were lower due to higher energy input and thus more intense reaction. Heating value was approximately 30 MJ/kg at a microwave power level of 250 W for 30 min processing time. The fuel ratio of torrefied leucaena was up to 3.7, which is much higher than that of bituminous coal and thus can be regarded as an alternative fuel to replace coal or co-fire with it. The energy return on investment of microwave torrefaction of leucaena can be 1.4, 17, and 34 when the handling capacities are 8, 100, and 200 g, respectively. Therefore, microwave torrefaction of leucaena is a promising technique that can be feasible if deployed at industrial scale. Activation energy and pre-exponential factor were 24.46 kJ/mol and 9.66 1/s, respectively.

In this study, microwave torrefaction of leucaena was studied to find out the potential applications and energy usage benefit of this technique. Both maximum temperature and heating rate increased with increasing microwave power level. Processing time was also an important operational parameter, but its effect was weaker than that of microwave power level. The heating value of torrefied product was higher at higher power level and longer processing time, but the mass and energy yields were lower due to higher energy input and thus more severe reaction. Heating value was approximately 30 MJ/kg at a microwave power level of 250 W for 30 min processing time. The fuel ratio of torrefied leucaena was up to 3.7, which is much higher than that of bituminous coal and thus can be regarded as an alternative fuel to replace or co-fire with coal. The energy return on investment of microwave torrefaction of leucaena can be 1.4, 17, and 34 when handling capacities are 8, 100, and 200 g, respectively. Therefore, microwave torrefaction of leucaena is a promising technique, and it can be more competitive when it is scaled up.

Reward value guides goal-directed behavior and modulates early sensory processing. Rewarding stimuli are often multisensory but it is not known how reward value is combined across sensory modalities. Here we show that the integration of reward value critically depends on whether the distinct sensory inputs are perceived to emanate from the same multisensory object. We systematically manipulated the congruency in monetary reward values and the relative spatial positions of co-occurring auditory and visual stimuli that served as bimodal distractors during an oculomotor task. The amount of interference induced by the distractors was used as an indicator of their perceptual salience. Our results across two experiments show that when reward value is linked to each modality separately, the value congruence between vision and audition determines the combined salience of the bimodal distractors. However, reward value of vision wins over the value of audition if visual and auditory stimuli have been experienced as belonging to the same audiovisual object prior to the learning of the reward values. The perceived spatial alignment of auditory and visual stimuli is a prerequisite for the integration of their reward values, as no effect of reward value was observed when the two modalities were perceived to be misaligned. These results show that in a task that highly relies on the processing of visual spatial information, the reward values from multiple sensory modalities are integrated with each other, each with their respective weights. This weighting depends on the congruency in reward values, exposure history, and spatial co-localization.

Various viruses have been studied and developed for oncolytic virotherapies. In virotherapy, a relatively small amount of viruses used in an intratumoral injection preferentially replicate in and lyse cancer cells, leading to the release of amplified viral particles that spread the infection to the surrounding tumor cells and reduce the tumor mass. Adenoviruses (Ads) are most commonly used for oncolytic virotherapy due to their infection efficacy, high titer production, safety, easy genetic modification, and well-studied replication characteristics. Ads with deletion of E1b55K preferentially replicate in and destroy cancer cells and have been used in multiple clinical trials. H101, one of the E1b55K-deleted Ads, has been used for the treatment of late-stage cancers as the first approved virotherapy agent. However, the mechanism of selective replication of E1b-deleted Ads in cancer cells is still not well characterized. This review will focus on three potential molecular mechanisms of oncolytic replication of E1b55K-deleted Ads. These mechanisms are based upon the functions of the viral E1B55K protein that are associated with p53 inhibition, late viral mRNA export, and cell cycle disruption.

Oncolytic adenoviruses (Ads) have been shown to be safe and have great potential for the treatment of solid tumors. However, the therapeutic efficacy of Ads is antagonized by limited spread within solid tumors. To develop Ads with enhanced spread, viral particles of an E1-wildtype Ad5 dl309 was repeatedly treated with UV type C irradiation and selected for the efficient replication and release from cancer cells. After 72 cycles of treatment and cancer selection, AdUV was isolated. This vector has displayed many favorable characteristics for oncolytic therapy. AdUV was shown to lyse cancer cells more effectively than both E1-deleted and E1-wildtype Ads. This enhanced cancer cell lysis appeared to be related to increased AdUV replication in and release from infected cancer cells. AdUV-treated A549 cells displayed greater expression of the autophagy marker LC3-II during oncolysis and formed larger viral plaques upon cancer cell monolayers, indicating increased virus spread among cancer cells. This study indicates the potential of this approach of irradiation of entire viral particles for the development of oncolytic viruses with designated therapeutic properties.

Background Clinical trials have indicated that preclinical results obtained with human tumor xenografts in mouse models may overstate the potential of adenovirus (Ad)-mediated oncolytic therapies. We have previously demonstrated that the replication of human Ads depends on cyclin E dysregulation or overexpression in cancer cells. ED-1 cell derived from mouse lung adenocarcinomas triggered by transgenic overexpression of human cyclin E may be applied to investigate the antitumor efficacy of oncolytic Ads. Methods Ad-cycE was used to target cyclin E overexpression in ED-1 cells and repress tumor growth in a syngeneic mouse model for investigation of oncolytic virotherapies. Results Murine ED-1 cells were permissive for human Ad replication and Ad-cycE repressed ED-1 tumor growth in immunocompetent FVB mice. ED-1 cells destroyed by oncolytic Ads in tumors were encircled in capsule-like structures, while cells outside the capsules were not infected and survived the treatment. Conclusion Ad-cycE can target cyclin E overexpression in cancer cells and repress tumor growth in syngeneic mouse models. The capsule structures formed after Ad intratumoral injection may prevent viral particles from spreading to the entire tumor. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1731-x) contains supplementary material, which is available to authorized users.

The Myc family of transcription factors (c-Myc, N-Myc, and L-Myc) are central mediators of many different critical cellular processes (1–4). Additionally, alteration of Myc is one of the most common genetic abnormalities in human cancers, including neuroblastoma (5). Unfortunately, the Myc protein has proven to be difficult to target directly in anticancer strategies. Myc activity is determined not only by its DNA binding sequences but also by local chromatin histone methylation status (6). Increased H3K4 methylation (active mark), but not H3K27 methylation (repressive mark), is characteristic of Myc-binding sites (6), which is consistent with recent studies that transcriptionally active epigenetic modifications mark genomic occupancy of Myc (7–9). An emerging theory is that Myc acts as a transcriptional amplifier, increasing transcription of genes that are already turned on, while genes not actively being transcribed are unaffected (8,9). However, two recent papers clearly demonstrated that Myc is also able to repress transcription (10,11). Nevertheless, Myc appears to be required for the induction and maintenance of normal histone methylation patterns associated with active chromatin in certain settings (12). Genetic disruption of MYCN in neural progenitors alters histone modifications that result in an increase in repressive H3K9me2/me3 marks and heterochromatinization, decreased DNA accessibility, and, ultimately, silencing of genes involved in Myc signaling (12), suggesting that Myc is required to maintain a euchromatin configuration by modifying histone methylation to facilitate its function. Similar results have been shown in cancer cells in which 12-hour inactivation of c-Myc resulted in global chromatin remodeling including elevated H3K9me3 (13). However, how H3K9me3/me2 is involved in mediating Myc function is not well understood. Additionally, the genetic alteration at glycine 34 (G34) of histone H3F3A, which is believed to affect the adjacent H3K36 methylation-related function, results in statistically significant N-Myc expression in pediatric glioblastoma (14), further supporting the biological connection between Myc activity and histone methylation. The JmjC domain-containing histone demethylases, which are responsible for reversing most of the histone methyl marks in the human genome, play important roles in a number of physiologic processes such as stem cell maintenance, cell cycle regulation, and oncogenesis (15–18). Besides somatic mutations identified in the genes encoding histone demethylases such as UTX (19,20) and JARID1C (21), aberrant expression of histone demethylases has been observed in various cancers (16,18). KDM4B/JMJD2B and KDM4C/JMJD2C, which catalyze the demethylation of the repressive H3K9me3/me2 mark, are amplified in medulloblastoma (22), malignant peripheral nerve sheath tumor (23), and squamous cell carcinoma (24), suggesting a role in the pathophysiology of these tumors. However, the contribution of these histone demethylases to the activity of oncogenic drivers such as Myc is uncertain. Additionally, the opportunity to exploit this relationship as a therapeutic strategy has yet to be explored.

Oncolytic virotherapy can selectively destroy cancer cells and is a potential approach in cancer treatment. A strategy to increase tumor-specific selectivity is to control the expression of a key regulatory viral gene with a tumor-specific promoter. We have previously found that cyclin E expression is augmented in cancer cells after adenovirus (Ad) infection. Thus, the cyclin E promoter that is further activated by Ad in cancer cells may have unique properties for enhancing oncolytic viral replication. We have shown that high levels of viral E1a gene expression are achieved in cancer cells infected with Ad-cycE, in which the endogenous Ad E1a promoter was replaced with the cyclin E promoter. Ad-cycE shows markedly selective oncolytic efficacy in vitro and destroys various types of cancer cells, including those resistant to ONYX-015/dl1520. Furthermore, Ad-cycE shows a strong capacity to repress A549 xenograft tumor growth in nude mice and significantly prolongs survival. This study suggests the potential of Ad-cycE in cancer therapy and indicates the advantages of using promoters that can be upregulated by virus infection in cancer cells in development of oncolytic viruses. Key messages: Cyclin E promoter activity is high in cancer cells and enhanced by adenovirus infection. Cyclin E promoter is used to control the E1a gene of a tumor-specific oncolytic adenovirus. Ad-cycE efficiently targets cancer cells and induces oncolysis. Ad-cycE significantly repressed xenograft tumor and prolonged survival.

Epidemiological studies suggest that high intake of cruciferous vegetables is associated with a lower risk of cancer. Experiments have shown that indole-3-carbinol (I3C), a naturally occurring compound derived from cruciferous vegetables, exhibits potent anticarcinogenic properties in a wide range of cancers. In this study, we showed that higher doses of I3C (≥400 μM) induced apoptotic cancer cell death and lower doses of I3C (≤200 μM) repressed cancer cell growth concurrently with suppressed expression of cyclin E and its partner CDK2. Notably, we found that pretreatment with low doses of I3C enhanced Ad-mediated oncolysis and cytotoxicity of human carcinoma cells by synergistic upregulation of apoptosis. Thus, the vegetable compound I3C as a dietary supplement may benefit cancer prevention and improve Ad oncolytic therapies.

Background: This study investigates the effect of altered auditory feedback (AAF) in musician's dystonia (MD) and discusses whether altered auditory feedback can be considered as a sensory trick in MD. Furthermore, the effect of AAF is compared with altered tactile feedback, which can serve as a sensory trick in several other forms of focal dystonia. Methods: The method is based on scale analysis (Jabusch et al. 2004). Experiment 1 employs synchronization paradigm: 12 MD patients and 25 healthy pianists had to repeatedly play C-major scales in synchrony with a metronome on a MIDI-piano with 3 auditory feedback conditions: 1. normal feedback; 2. no feedback; 3. constant delayed feedback. Experiment 2 employs synchronization-continuation paradigm: 12 MD patients and 12 healthy pianists had to repeatedly play C-major scales in two phases: first in synchrony with a metronome, secondly continue the established tempo without the metronome. There are 4 experimental conditions, among them 3 are the same altered auditory feedback as in Experiment 1 and 1 is related to altered tactile sensory input. The coefficient of variation of inter-onset intervals of the key depressions was calculated to evaluate fine motor control. Results: In both experiments, the healthy controls and the patients behaved very similarly. There is no difference in the regularity of playing between the two groups under any condition, and neither did AAF nor did altered tactile feedback have a beneficial effect on patients’ fine motor control. Conclusions: The results of the two experiments suggest that in the context of our experimental designs, AAF and altered tactile feedback play a minor role in motor coordination in patients with musicians' dystonia. We propose that altered auditory and tactile feedback do not serve as effective sensory tricks and may not temporarily reduce the symptoms of patients suffering from MD in this experimental context.

Adenoviruses (Ads) with deletion of E1b55K preferentially replicate in cancer cells and have been used in cancer therapies. We have previously shown that Ad E1B55K protein is involved in induction of cyclin E for Ad replication, but this E1B55K function is not required in cancer cells in which deregulation of cyclin E is frequently observed. In this study, we investigated the interaction of cyclin E and CDK2 in Ad-infected cells. Ad infection significantly increased the large form of cyclin E (cyclin EL), promoted cyclin E/CDK2 complex formation and increased CDK2 phosphorylation at the T160 site. Activated CDK2 caused pRb phosphorylation at the S612 site. Repression of CDK2 activity with the chemical inhibitor roscovitine or with specific small interfering RNAs significantly decreased pRb phosphorylation, with concomitant repression of viral replication. Our results suggest that Ad-induced cyclin E activates CDK2 that targets the transcriptional repressor pRb to generate a cellular environment for viral productive replication. This study reveals a new molecular basis for oncolytic replication of E1b-deleted Ads and will aid in the development of new strategies for Ad oncolytic virotherapies.